In the era of growing antibiotic resistance, life threatening infections with several bacterial pathogens are cause for major concern. Approved vaccines exist only for a handful of bacterial pathogens. Even when a vaccine is available invasive bacterial diseases can occur due to lack of serotype coverage, poor vaccine response among vaccinated populations, or because many simply don?t get vaccinated. Thus, innovative concepts are needed to cope with these challenges. The current proposal is aimed at developing a novel post exposure treatment that is serotype independent and can be applied to a variety of gram positive bacteria. The approach, termed Infection Site Targeted universal Bridging Antigen (ISTuBA) exploits the ability of species-specific, but serotype- independent, phage-derived bacterial cell wall binding domains (CBD) to target an ?ImmunoBridge?, an antigen against which most people have antibodies, to the surface of bacteria. The CBD will redirect the pre-existing immunity against ImmunoBridge towards the new invading pathogen leading to clearance of infection. In this proposal prototype ISTuBAs will be created for Streptococcus pneumoniae, the leading cause of community acquired pneumonia as well other life-threatening infections. In preliminary studies we have demonstrated that ISTuBAs based on an attenuated staphylococcal enterotoxin B vaccine (STEBVax) as ImmunoBridge and S. pneumoniae specific CBDs can direct an S. aureus specific antibody response to mediate opsonophagocytosis of S. pneumoniae strains. Building upon these strong preliminary data, in Aim 1 we will test a wide range of candidate CBDs for binding against a broad panel of pneumococcal serotypes to identify the best CBDs. A short list of broadly reactive CBDs with high affinity will be used to create candidate ISTuBAs in Aim 2 using not only STEBVax but also diphtheria toxoid (CRM197) and Tetanus toxoid as ImmunoBridge. The candidate ISTuBAs will be thoroughly characterized for biochemical and functional properties including opsonophagocytosis in presence of anti-ImmunoBridge antibodies. Two best ISTuBA candidates will be tested in mouse intranasal model of S. pneumoniae infection in Aim 3. Upon successful completion of Phase I we anticipate a Phase II project that will focus on optimization of the constructs, extensive efficacy testing in both pneumonia and sepsis models, formulation, pharmacokinetics and other IND-enabling studies.